The long-term goal of this proposal is to provide insight into mechanisms critical for stress-facilitated memory formation, or in other words, the processing of memories under stressful conditions. Two stress- and memory-associated disorders, posttraumatic stress disorder and major depressive disorder, are prime examples of disorders with abnormal stress-facilitated memory processing, and they both have an estimated lifetime prevalence of over 5% among Americans. A key signaling pathway implicated in stress-induced memory processing is the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Activation of this pathway leads to downstream activation of cAMP response element-binding protein, which results in transcriptional changes needed to form new memories. The activator of the MAPK/ERK pathway that modulates stress-facilitated memory is still not well defined. However, evidence suggests the second messenger, cAMP, may be the upstream initiator as cAMP production can activate this pathway to cause changes in memory. Moreover, calcium-stimulated adenylyl cyclases (AC), AC1 and AC8, couple neuronal activity and intracellular calcium increases to the production of cAMP, thus, implicating calcium-stimulated AC activity in modulating stress-facilitated memory changes. As a paradigm for stress-facilitated memory, we will use a classical conditioning test, which serves as a good model to investigate our hypothesis as both the MAPK/ERK signaling pathway and calcium-stimulated AC activity have been shown to effect learning on this paradigm. Therefore, we aim to examine how this activity may activate the MAPK/ERK pathway to modulate stress-facilitated memory. Through use of a novel transgenic mouse model, which uses a tetracycline-inducible system to replace AC8 expression in AC1 and AC8 double knock-out mice, we are able to assess the time-specific importance of this activity. Moreover, through the use of gene therapy techniques, we can assess the region-specific importance of this activity via lentivirus administration that turns on AC8 expression. Relevance: The research we are proposing will give insight into a mechanism of memory formation under stressful conditions and may reveal a primary role of memory-related symptoms in psychiatric disorders. More specifically, it will look at the time- and region-specific manner in which this stress-facilitated memory mechanism modulates memory formation. This work may eventually lead to the development of therapeutic interventions for people with abnormal memory changes from stress-related disorders as global, non-specific treatments can facilitate a host of unwanted side-effects. PUBLIC HEALTH RELVENCE The research we are proposing will give insight into a mechanism of memory formation under stressful conditions and may reveal a primary role of memory-related symptoms in psychiatric disorders. More specifically, it will look at the time- and region-specific manner in which this stress-facilitated memory mechanism modulates memory formation. This work may eventually lead to the development of therapeutic interventions for people with abnormal memory changes from stress-related disorders as global, non- specific treatments can facilitate a host of unwanted side-effects.